Kotaro Nochioka

Heart failure as a general pandemic in Asia.

Heart failure (HF) is an epidemic in healthcare worldwide, including Asia. It appears that HF will become more serious in the near future, with the epidemiological transition and ageing of the population. However, in contrast to Western countries, information on HF epidemiology is still limited in Asia, particularly in South Asia. In this review, we will briefly summarize available information regarding the current and future burden of HF in Asia, which indicates the importance of both primary prevention of underlying diseases of HF and secondary prevention, including management of ischaemic HF, HF with preserved EF, and HF in the elderly.

Global Longitudinal Strain Is a Superior Predictor of All-Cause Mortality in Heart Failure With Reduced Ejection Fraction

OBJECTIVES The purpose of this study was to investigate the prognostic value of global longitudinal strain (GLS) in heart failure with reduced ejection fraction (HFrEF) patients in relation to all-cause mortality. BACKGROUND Measurement of myocardial deformation by 2-dimensional speckle tracking echocardiography, specifically GLS, may be superior to conventional echocardiographic parameters, including left ventricular ejection fraction, in predicting all-cause mortality in HFrEF patients. METHODS Transthoracic echocardiographic examinations were retrieved for 1,065 HFrEF patients admitted to a heart failure clinic. The echocardiographic images were analyzed, and conventional and novel echocardiographic parameters were obtained. RESULTS Many of the conventional echocardiographic parameters proved to be predictors of mortality. However, GLS remained an independent predictor of mortality in the multivariable model after adjusting for age, sex, body mass index, total cholesterol, mean arterial pressure, heart rate, ischemic cardiomyopathy, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, noninsulin dependent diabetes mellitus, and conventional echocardiographic parameters (hazard ratio [HR]: 1.15; 95% confidence interval [CI]: 1.04 to 1.27; p = 0.008, per 1% decrease). No other echocardiographic parameter remained an independent predictor after adjusting for these variables. Furthermore, GLS had the highest C-statistics of all the echocardiographic parameters and added incremental prognostic value with a significant increase in the net reclassification improvement (p = 0.009). Atrial fibrillation (AF) modified the relationship between GLS and mortality (p value for interaction = 0.036); HR: 1.08 (95% CI: 0.97 to 1.19), p = 0.150 and HR: 1.22 (95% CI: 1.15 to 1.29), p < 0.001, per 1% decrease in GLS for patients with and without AF, respectively. Sex also modified the relationship between GLS and mortality (p value for interaction = 0.047); HR: 1.23 (95% CI: 1.16 to 1.30), p < 0.001 and HR: 1.09 (95% CI: 0.99 to 1.20), p = 0.083, per 1% decrease in GLS for men and women, respectively. CONCLUSIONS GLS is an independent predictor of all-cause mortality in HFrEF patients, especially in male patients without AF. Furthermore, GLS was a superior prognosticator compared with all other echocardiographic parameters.

Statins Exert the Pleiotropic Effects Through Small GTP-Binding Protein Dissociation Stimulator Upregulation With a Resultant Rac1 Degradation

Objective—The pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) independent of cholesterol-lowering effects are thought to be mediated through inhibition of the Rho/Rho-kinase pathway. However, we have previously demonstrated that the pleiotropic effects of regular-dose statins are mediated mainly through inhibition of the Rac1 signaling pathway rather than the Rho/Rho-kinase pathway, although the molecular mechanisms of the selective inhibition of the Rac1 signaling pathway by regular-dose statins remain to be elucidated. In this study, we tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by statins in endothelial cells. Approach and Results—In cultured human umbilical venous endothelial cells, statins concentration-dependently increased SmgGDS expression and decreased nuclear Rac1. Statins also enhanced SmgGDS expression in mouse aorta. In control mice, the protective effects of statins against angiotensin II–induced medial thickening of coronary arteries and fibrosis were noted, whereas in SmgGDS-deficient mice, the protective effects of statins were absent. When SmgGDS was knocked down by its small interfering RNA in human umbilical venous endothelial cells, statins were no longer able to induce Rac1 degradation or inhibit angiotensin II–induced production of reactive oxygen species. Finally, in normal healthy volunteers, statins significantly increased SmgGDS expression with a significant negative correlation between SmgGDS expression and oxidative stress markers, whereas no correlation was noted with total or low-density lipoprotein-cholesterol. Conclusions—These results indicate that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.

Basigin Mediates Pulmonary Hypertension by Promoting Inflammation and Vascular Smooth Muscle Cell Proliferation

Rationale: Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells (VSMCs) by oxidative stress and promotes VSMC proliferation. However, the role of extracellular CyPA and its receptor Basigin (Bsg, encoded by Bsg) in the pathogenesis of pulmonary hypertension (PH) remains to be elucidated. Objective: To determine the role of CyPA/Bsg signaling in the development of PH. Methods and Results: In the pulmonary arteries of patients with PH, immunostaining revealed strong expression of CyPA and Bsg. The pulmonary arteries of CyPA+/– and Bsg+/– mice exposed to normoxia did not differ in morphology compared with their littermate controls. In contrast, CyPA+/– and Bsg+/– mice exposed to hypoxia for 4 weeks revealed significantly reduced right ventricular systolic pressure, pulmonary artery remodeling, and right ventricular hypertrophy compared with their littermate controls. These features were unaltered by bone marrow reconstitution. To further evaluate the role of vascular Bsg, we harvested pulmonary VSMCs from Bsg+/+ and Bsg+/– mice. Proliferation was significantly reduced in Bsg+/– compared with Bsg+/+ VSMCs. Mechanistic studies demonstrated that Bsg+/– VSMCs revealed reduced extracellular signal–regulated kinase 1/2 activation and less secretion of cytokines/chemokines and growth factors (eg, platelet-derived growth factor-BB). Finally, in the clinical study, plasma CyPA levels in patients with PH were increased in accordance with the severity of pulmonary vascular resistance. Furthermore, event-free curve revealed that high plasma CyPA levels predicted poor outcome in patients with PH. Conclusions: These results indicate the crucial role of extracellular CyPA and vascular Bsg in the pathogenesis of PH.

Urinary albumin excretion in heart failure with preserved ejection fraction: an interim analysis of the CHART 2 study

Heart failure with preserved ejection fraction (HFpEF) is characterized by multiple co‐morbidities, including chronic kidney disease that is one of the prognostic risks for these patients. This study was performed to evaluate the value of determination of albuminuria using a urine dipstick test (UDT), combined with estimated glomerular filtration rate (eGFR), for predicition of mortality in HFpEF.

Temporal Trends in Clinical Characteristics, Management and Prognosis of Patients With Symptomatic Heart Failure in Japan – Report From the CHART Studies –

BACKGROUND Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan. METHODSANDRESULTS From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%. CONCLUSIONS Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. ( TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00418041)

Characterization of heart failure patients with mid-range left ventricular ejection fraction—a report from the CHART-2 Study

The new category of heart failure (HF), HF with mid‐range left ventricular ejection fraction (LVEF) (HFmrEF), has recently been proposed. However, the clinical features of HFmrEF, with reference to HF with preserved LVEF (HFpEF) and HF with reduced LVEF (HFrEF) in the same HF cohort, remain to be fully examined.

Prognostic Impact of Statin Use in Patients With Heart Failure and Preserved Ejection Fraction

BACKGROUND The effectiveness of statins remains to be examined in patients with heart failure (HF) with preserved ejection fraction (EF). METHODS AND RESULTS: Among 4,544 consecutive HF patients registered in the Chronic Heart Failure Registry and Analysis in the Tohoku district-2 (CHART-2) between 2006 and 2010, 3,124 had EF ≥50% (HFpEF; mean age 69 years; male 65%) and 1,420 had EF <50% (HF with reduced EF (HFrEF); mean age 67 years; male 75%). The median follow-up was 3.4 years. The 3-year mortality in HFpEF patients was lower in patients receiving statins [8.7% vs. 14.5%, adjusted hazard ratio (HR) 0.74; 95% confidence interval (CI), 0.58-0.94; P<0.001], which was confirmed in the propensity score-matched cohort (HR, 0.72; 95% CI, 0.49-0.99; P=0.044). The inverse probability of treatment weighted further confirmed that statin use was associated with reduced incidence of all-cause death (HR, 0.71; 95% CI, 0.62-0.82, P<0.001) and noncardiovascular death (HR, 0.53; 95% CI, 0.43-0.66, P<0.001), specifically reduction of sudden death (HR, 0.59; 95% CI, 0.36-0.98, P=0.041) and infection death (HR, 0.53; 95% CI, 0.35-0.77, P=0.001) in HFpEF. In the HFrEF cohort, statin use was not associated with mortality (HR, 0.87; 95% CI, 0.73-1.04, P=0.12), suggesting a lack of statin benefit in HFrEF patients. CONCLUSIONS These results suggest that statin use is associated with improved mortality rates in HFpEF patients, mainly attributable to reductions in sudden death and noncardiovascular death.

Enhanced [18F]fluorodeoxyglucose accumulation in the right ventricular free wall predicts long-term prognosis of patients with pulmonary hypertension: a preliminary observational study.

AIMS We have previously demonstrated that [(18)F]fluorodeoxyglucose (FDG) accumulation is increased in the right ventricular (RV) free wall of patients with pulmonary hypertension (PH), and that this accumulation is ameliorated after the treatment with epoprostenol associated with improvement of haemodynamic overload. The aim of this study was to examine whether enhanced RV FDG accumulation by gated positron emission tomography (PET) has a prognostic impact in patients with PH. METHODS AND RESULTS We examined the prognostic impact of the RV standardized uptake value (SUV) of FDG-PET corrected for the partial volume effect (cRV-SUV) in 27 patients with PH who underwent gated FDG-PET from March 2001 to June 2004. During the follow-up period of 69 ± 49 (mean ± SD) months, among the 27 patients, 15 showed clinical worsening (CW) and 11 died. FDG-PET examination showed that cRV-SUV was significantly higher in the CW group compared with the non-CW group (10.1 vs. 7.6, P = 0.02). Univariate Cox hazard analysis showed that cRV-SUV was significantly correlated with the time to CW (hazard ratio 1.25, 95% confidence interval 1.04-1.51, P = 0.02), which remained significant even after adjustment of World Health Organization functional class. Kaplan-Meier analysis showed that the patients with cRV-SUV ≥8.3 had poor prognosis compared with those with cRV-SUV <8.3 (log-rank P = 0.005 for time to CW and P = 0.07 for mortality). CONCLUSION These results indicate that enhanced FDG accumulation in the RV free wall may be a novel prognostic factor in patients with PH.

Both High and Low Body Mass Indexes are Prognostic Risks in Japanese Patients With Chronic Heart Failure: Implications From the CHART Study

BACKGROUND Prognostic impact of body mass index (BMI) in Japanese patients with chronic heart failure (HF) remains unclear. METHODS AND RESULTS We examined the relationship between BMI and the prognosis of Japanese HF patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART) study. The study sample was 972 Japanese chronic HF patients (mean age, 68.2 ± 13.5; male 65.2%). We categorized them into 5 groups; BMI <18.5, 18.5 to 22.9, 23.0 to 24.9 (reference), 25.0 to 29.9, and ≥ 30.0. Using a Cox hazards model, the relationships between BMI and deaths or admission for worsening HF were studied in detail. Mean follow-up period was 3.4 ± 1.7 years. Multivariate analysis showed that, as compared with reference group (BMI 23.0 to 24.9), hazard ratios (HR) for all-cause death showed a U-shaped association with 1.70 (95% confidence interval; 1.04-2.76), 1.23 (0.85-1.78), 1.26 (0.84-1.90), and 2.75 (1.51-5.00) among those with BMI<18.5, 18.5 to 22.9, 25.0 to 29.9, and ≥ 30.0, respectively. There were significant and suggestive U-shaped associations between BMI and cardiac-cause death or admission for worsening HF. CONCLUSIONS Both high and low BMIs were associated with increased outcomes, suggesting that extreme obesity is not beneficial in improving the prognosis of Japanese chronic HF patients.